new diagnostic molecular markers and biomarkers in
TRANSCRIPT
Vol.:(0123456789)1 3
Molecular Biology Reports (2021) 48:3617–3628 https://doi.org/10.1007/s11033-021-06286-0
REVIEW
New diagnostic molecular markers and biomarkers in odontogenic tumors
Alieh Farshbaf1,2 · Reza Zare3 · Farnaz Mohajertehran1,2,3 · Nooshin Mohtasham3
Received: 9 January 2021 / Accepted: 11 March 2021 / Published online: 6 April 2021 © The Author(s), under exclusive licence to Springer Nature B.V. 2021
AbstractOdontogenic tumors comprised of complex heterogeneous lesions that diverse from harmatomas to malignant tumors with different behavior and histology. The etiology of odontogenic tumors is not exactly determined and pathologists deal with challenges in diagnosis of odontogenic tumors because they are rare and obtained experiences are difficult to evaluate. In this study, we describe immunohistochemical and molecular markers in diagnosis of odontogenic tumors besides advanced diagnostic technique. Immunohistochemical features of odontogenic tumors beside the clinical features and radiological finding can help us to determine the correct diagnosis. Although these markers are neither specific nor sensitive enough, but analysis of gene expression provides definitive confirmation of diagnosis. In addition, “-omics” technology detected specific molecular alternation associated with etiology such as genomics, epigenomics, transcriptomics, proteomics and metabo-lomics. The post transcriptional events such as DNA methylation and chromatin remodeling by histone modification affect the changes in epigenome. Furthermore, non-coding RNAs like micro-RNAs, long noncoding RNA (lncRNA) and small non-coding RNA (snoRNA) play regulatory role and impact odontogenesis. Molecular marker propose their potential role in etiopathogenesis of odontogenic tumors and suitable candidate in diagnostic, prognostic and therapeutic approaches in addition to patient management. For future evaluations, organoid represents in vitro tumor model-study for tumor behavior, metastasis and invasion, drug screening, immunotherapy, clinical trial, hallmarks association with prognosis and evolution of personalized anti-cancer therapy. Moreover, organoid biobank help us to check genetic profile. We think more investigation and studies are needed to gain these knowledges that can shift therapeutic approaches to target therapy.
Keywords Odontogenic tumor · Immunohistochemistry · Molecular marker · Biomarker · Oral lesions
Introduction
Odontogenic tumors comprise of complex heterogeneous lesions that originate from ectomesenchymal and/or epithe-lial odontogenic tissues and manifest following normal tooth development. They are diverse from harmatomas to malig-nant tumors with different behavior, histology and even dif-ferent geographical distribution [1]. The odontogenic tumors
manifest variant clinical features including disfigurement of the face, jaw expansion and extension, root and bone resorp-tions, teeth mobility and alternation in bone density [2]. There are two primary classification for odontogenic tumors including benign odontogenic tumors that arise de novo and malignant odontogenic tumors that almost take from benign precursor, but WHO categorized the new edition based on origin of tissue and histological characteristics in 2017 that are mentioned in Table 1 [3, 4]. It was reported that among all oral tumors, odontogenic tumors are less than 1%, and also 99.2% of them are benign type [5].
Markers are molecules, genes or molecular features in pathogenesis of disease play a critical role in diagnosis and management of patients, especially in tumorigenic cases [6]. It was identified a few markers for evaluation of odontogenic tumor s pathogenesis, but immunohistochemistry (IHC) may be useful for pathologists. Although histological fea-tures of odontogenic tumor such as morphology along with
* Nooshin Mohtasham [email protected]
1 Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
3 Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3618 Molecular Biology Reports (2021) 48:3617–3628
1 3
Tabl
e 1
The
last
WH
O c
lass
ifica
tion
of o
dont
ogen
ic tu
mor
s (20
17) w
ith d
iagn
ose
and
prog
nose
s fea
ture
s
Odo
ntog
enic
tum
orC
linic
al fe
atur
eH
istop
atho
logi
c fe
atur
eD
iffer
entia
l dia
gnos
isPr
ogno
sis a
nd tr
eatm
ent
Odo
ntog
enic
car
cino
ma
Am
elob
lasti
c ca
rcin
oma
Irre
gula
r mar
gina
ted
radi
oluc
ency
. co
rtica
l exp
ansi
on, p
erfo
ratio
n an
d in
filtra
tion
into
adj
acen
t stru
ctur
es
Hist
olog
ical
cha
ract
ers o
f mal
ig-
nanc
y in
am
elob
lasto
ma
- Any
odo
ntog
enic
tum
or w
ith
amel
obla
stic
diffe
rent
iatio
n- I
n 1/
3 of
pat
ient
met
asta
sis t
o pu
lmon
ary
- Mos
t sur
viva
l age
is ~
5 ye
ars
- prim
ary
treat
men
t: ra
dica
l sur
gica
l ex
cisi
on- a
ggre
ssiv
e m
ultim
odal
ity fr
om th
e ou
tset
Prim
ary
intra
osse
ous c
arci
nom
a (P
IOC
), N
OS
Slow
gro
win
g of
, pai
n, u
lcer
atio
n,
loos
enin
g of
teet
h, n
on-h
ealin
g ex
tract
ion
sock
et, a
nd p
atho
logi
cal
frac
ture
and
ner
ve si
gns
smal
l nes
t of n
eopl
astic
squa
mou
s w
ithou
t pro
min
ent k
erat
iniz
atio
nSq
uam
ous o
dont
ogen
ic tu
mor
s,int
ra
osse
ous m
ucoe
pide
rmoi
d ca
rcin
oma,
prim
ary
jaw
SC
C
- bes
t pre
dict
ed b
y hi
stolo
gica
l gra
de- p
rimar
y tre
atm
ent:
radi
cal r
esec
tion
with
nec
k di
ssec
tion
or fo
r met
asta
-si
s or r
econ
struc
tion
- mul
timod
ality
trea
tmen
tSc
lero
sing
odo
ntog
enic
car
cino
ma
(SO
C)
Swel
ling,
som
etim
es w
ith n
erve
si
gn, s
inus
invo
lvem
ent
Sing
le-fi
le th
in c
ords
, nes
ts a
nd
stran
ds o
f epi
thel
ium
in a
den
sely
sc
lero
tic st
rom
a
- Cal
cify
ing
epith
elia
l odo
ntog
enic
tu
mor
- Des
mop
lasti
c am
elob
lasto
ma
- Mai
n tre
atm
ent:
rese
ctio
n
Cle
ar c
ell o
dont
ogen
ic c
arci
nom
aA
lmos
t are
asy
mpt
omat
icLo
bula
r she
ets o
r isl
ands
com
pose
d of
cle
ar to
fain
tly e
osin
ophi
lic
cyto
plas
m
Pind
borg
tum
or (c
lear
cel
l typ
e),
intra
oss
eous
muc
oepi
derm
oid
carc
inom
a
- Var
iant
beh
avio
r fro
m in
dole
nt
tum
ors t
o ca
ses t
hat f
requ
ently
recu
r- C
ompl
ete
surg
ical
rese
ctio
nG
host
cell
odon
toge
nic
carc
inom
a (G
COC
)Sl
ow g
row
ing,
swel
ling
of th
e ja
w,
pain
, ulc
erat
ion,
loos
ing
of te
eth,
ne
rve
sign
s, ro
ot re
sorp
tion
and
som
etim
es so
ft tis
sue
inva
sion
cyto
logi
cal e
vide
nces
of m
alig
nanc
y as
soci
ated
with
gho
st ce
lls, d
enti-
noid
form
atio
n
from
slow
gro
win
g, lo
cally
inva
sive
ca
rcin
omas
to h
ighl
y ag
gres
sive
and
ra
pidl
y gr
owin
g tu
mor
s with
loca
l re
curr
ence
and
met
asta
sis
Odo
ntog
enic
car
cino
sarc
oma
Odo
ntog
enic
sarc
omas
Beni
gn e
pith
elia
l odo
ntog
enic
tum
ors
Am
elob
lasto
ma:
Slow
and
pai
nles
s loo
seni
ng o
f te
eth,
par
aest
hesi
a, p
ain,
soft
tissu
e in
vasi
on, f
acia
l def
orm
ity, l
imite
d m
outh
ope
ning
Am
elob
lasti
c di
ffere
ntia
tion,
reve
rse
pola
rity
and
cent
ral l
oose
ly
arra
nged
, ste
llate
cel
ls
- Any
odo
ntog
enic
lesi
on w
ith
amel
obla
stic
diffe
rent
iatio
n- C
urre
nt tr
eatm
ent:
surg
ical
exc
isio
n- N
ew th
erap
eutic
app
roac
h ba
sed
on
BRAF
targ
etin
g co
mpl
emen
t sur
gery
Am
elob
lasto
ma,
uni
cysti
c ty
pe
(UA
M)
- Asy
mpt
omat
ic p
ainl
ess j
aw e
xpan
-si
on- U
nilo
cula
r rad
iolu
cenc
y
- Lum
inal
, int
ralu
min
al ty
pes
odon
toge
nic
cysts
- ben
ign
odon
toge
nic
tum
ors
- Ini
tial t
reat
men
t: en
ucle
atio
n- F
urth
er tr
eatm
ent i
s det
erm
ined
by
patte
rn a
nd e
xten
d of
the
amel
obla
s-to
mat
ous p
rolif
erat
ion
Am
elob
lasto
ma,
ext
raos
seou
s/
perip
hera
l typ
e- P
ainl
ess,
sess
ile, e
xoph
ytic
lesi
onam
elob
lasti
c di
ffere
ntia
tion,
reve
rse
pola
rity
and
cent
ral l
oose
ly
arra
nged
, ste
llate
cel
ls
- Per
iphe
ral o
dont
ogen
ic le
sion
s- R
eact
ive
lesi
ns- C
onse
rvat
ive
rem
oval
with
free
mar
-gi
ns is
exp
ecte
d to
be
cura
tive
- Rec
urre
nce
is ra
re, b
ut lo
ng te
m fo
l-lo
w u
p is
war
rant
edM
etas
tasi
zing
am
elob
lasto
ma
- Mor
e de
term
ined
by
clin
ical
be
havi
or- D
iagn
osis
mad
e on
ly in
retro
spec
t af
ter o
ccur
renc
e of
met
asta
sis
Hist
olog
ical
feat
ures
of p
rimar
y an
d m
etas
tasi
zing
are
sim
ilar
- Con
vent
iona
l sol
id o
r mul
ticys
tic
amel
obla
stom
a- T
he o
vera
ll 5-
year
surv
ival
rate
is
depe
nd o
n th
e si
te o
f met
asta
sis a
nd
surg
ical
acc
essi
bilit
y
3619Molecular Biology Reports (2021) 48:3617–3628
1 3
Tabl
e 1
(con
tinue
d)
Odo
ntog
enic
tum
orC
linic
al fe
atur
eH
istop
atho
logi
c fe
atur
eD
iffer
entia
l dia
gnos
isPr
ogno
sis a
nd tr
eatm
ent
Squa
mou
s odo
ntog
enic
tum
or (S
OT)
- Asy
mpt
omat
ic- T
umor
gro
w sl
owly
with
bon
e ex
pans
ion
- Uni
locu
lar r
adio
luce
ncy
Diff
eren
tiate
d sq
uam
ous e
pith
eliu
m
of v
aryi
ng sh
ape
and
size
cell
kera
tiniz
atio
n
- Aca
ntho
mat
ous A
mel
obla
stom
a-d
esm
opla
stic
varia
nts
-squ
amou
s cel
l car
cino
ma
- Rem
ove
by su
rger
y- R
ecur
renc
e is
rare
Cla
ssify
epi
thel
ial o
dont
ogen
ic
tum
or (C
EOT)
grow
s slo
wly
with
bon
e ex
pans
ion
- Uni
locu
lar o
r mul
tiocu
lar m
ixed
ra
diol
ucen
cy
isla
nds,
cord
s and
shee
ts o
f neo
plas
-tic
pol
yhed
ral e
pith
elia
l cel
ls w
ith
rela
tive
pleo
mor
phis
m, l
iese
gang
rin
gs, w
ithou
t pro
min
ent m
itotic
ac
tivity
- Prim
ary
intra
osse
ous s
quam
ous
cell
carc
inom
a-C
entra
l muc
oepi
derm
oid
car-
cino
ma,
met
asta
tic re
nal c
ell
carc
inom
a, c
lear
cel
l odo
ntog
enic
ca
rcin
oma
- mos
t cas
es tr
eate
d w
ith lo
cal s
urgi
-ca
l rem
oval
- rec
urre
nce
rate
is a
bout
15%
Ade
nom
atio
d od
onto
geni
c tu
mor
(A
OT)
- Lim
it gr
owth
but
man
y ha
mar
to-
mas
- sym
ptom
atic
with
/with
out b
ony
expa
nsio
n- s
mal
l loc
i of r
adio
paci
ty
- enc
apsu
late
d sp
indl
ed e
pith
elia
l ce
lls, R
osse
tte o
r duc
t lik
e sp
aces
,- E
osin
ophi
lic m
ater
ial w
ithin
tum
or
like
secr
etio
n pr
oduc
t
- Odo
ntom
a- A
mel
obla
stom
aC
lass
ifyin
g ep
ithel
ial o
dont
ogen
ic
tum
or
- The
y ar
e en
caps
ulat
ed a
nd e
nvar
i-ab
ly e
nucl
eate
d- R
ecur
renc
e ra
tes a
re e
xcee
ding
low
Beni
gn m
ixed
epi
thel
ial a
nd m
esen
chym
al o
dont
ogen
ic tu
mor
sA
mel
obla
stic
fibro
ma
(AF)
- Slo
w g
row
ing,
pai
nles
s- U
nilo
cula
r rad
iolu
cenc
y, m
ultic
ular
re
late
d to
larg
er le
sion
s
- Mes
ench
ymal
com
pone
nt: m
yxoi
d,
cell-
rich
and
rese
mbl
ed th
e de
ntal
pa
pilla
of t
he to
oth
bud
- Epi
thel
ial c
ompo
nent
: pat
tern
of
narr
ow, e
long
ated
stra
nds o
f tw
o tig
ht a
nd p
aral
lel-r
unni
ng w
ith
budd
ing,
laye
rs o
f cub
oida
l to
colu
mna
r cel
l or a
ssem
bled
fol-
licul
ar st
age
of e
nam
el
- Ear
ly st
age
odon
tom
a-E
arly
stag
eAm
elob
lasti
c fib
rood
on-
tom
a- A
mel
obla
stom
a
- Sm
all,
asym
ptom
atic
tum
ors
(esp
ecia
lly in
you
ng c
hild
ren)
are
re
mov
ed c
onse
rvat
ivel
y; h
owev
er,
ulte
raco
nser
vativ
e tre
atm
ent m
ight
re
sult
in re
curr
ence
- Ext
ensi
ve, d
estru
ctiv
e tu
mor
s tre
ated
ra
dica
lly
Prim
ordi
al o
dont
ogen
ic tu
mor
- An
uner
upte
d to
oth
(mos
t com
-m
only
the
low
er th
ird m
olar
) with
ap
pare
nt p
eric
oron
al re
latio
nshi
p on
radi
ogra
phic
al im
age
- Mos
t asy
mpt
omat
ic
loos
e fib
rous
tiss
ue w
ith v
aria
nt
fusi
form
and
stel
late
fibr
obla
st an
d pe
riphe
ral c
olum
nar/c
uboi
dal
epith
eliu
m
- Odo
ntog
enic
myx
oma
- Am
elob
lasti
c fib
rom
a- C
ente
ral o
dont
ogen
ic fi
brom
a
- loc
al e
xcis
ion
- no
recu
rren
ce u
ntil
20 y
ears
3620 Molecular Biology Reports (2021) 48:3617–3628
1 3
Tabl
e 1
(con
tinue
d)
Odo
ntog
enic
tum
orC
linic
al fe
atur
eH
istop
atho
logi
c fe
atur
eD
iffer
entia
l dia
gnos
isPr
ogno
sis a
nd tr
eatm
ent
Odo
ntom
a:O
dont
oma,
com
poun
d ty
peO
dont
oma,
com
plex
type
- Rel
ated
to u
neru
pted
toot
h an
d de
tect
able
in ra
diog
raph
s- A
sym
ptom
atic
but
may
infla
med
du
ring
traum
a or
eru
ptio
n- W
ell-d
emar
cate
d ra
diop
acity
su
rrou
nded
by
a th
in so
ft tis
sue
caps
ule
and
an a
djac
ent c
ortic
ated
la
yer o
f bon
e- R
adio
logi
cal f
eatu
res:
Com
poun
d ty
pe: d
iagn
ostic
, man
y to
oth-
like
struc
ture
s. co
mpl
ex ty
pe:
diso
rgan
ized
mas
s of c
lass
ified
tis
sues
mig
ht in
disti
ngui
sh fr
om
othe
r cla
ssifi
ed b
one
lesi
ons
- Com
poun
d ty
pe: m
ultip
le ru
dim
en-
tary
teet
h de
mon
strat
ing
dent
in,
cem
entu
m, e
nam
el m
atrix
, pul
p an
d ad
jace
nt fi
brou
s with
den
tal
folli
cle
- Com
plex
type
: tub
ular
den
tin
encl
osed
zon
es o
f ena
mel
mat
rix,
decr
ease
d en
amel
epi
thel
ium
with
in
freq
uent
scat
tere
d gh
ost c
ell
- A n
arro
w la
yer o
f cem
entu
m in
pe
riphe
ral o
f mas
s
- Am
elob
lasti
c fib
rom
a-O
dont
oam
elob
lasto
ma
- Rem
ove
by c
onse
rvat
ive
surg
ery
if be
low
gro
wth
- Pro
gnos
is is
exc
elle
nt
Den
tinog
enic
gho
st ce
ll tu
mor
(D
GC
T)- c
ortic
al b
one
expa
nsio
n- u
nilo
cula
r or m
ultil
ocul
ar ra
dio-
luce
ncy
radi
oluc
ent,m
ixed
or r
adio
paqu
e,w
ell d
efine
d bo
rder
- Odo
ntog
enic
epi
thel
ium
with
are
as
clos
ely
rese
mbl
ing
amel
obla
stom
a- P
rese
nce
of g
host
cells
: Abb
eran
t ke
ratin
izat
ion
with
cal
cific
atio
n
Am
elob
lasto
ma
with
gho
st ce
ll- r
ecom
men
ded
treat
men
t: se
gmen
tal
surg
ury
- Con
serv
ativ
e su
rger
y (e
nucl
eatio
n,
cure
ttage
/sim
ple
exci
sion
), ra
te o
f re
curr
ence
: 73%
unt
il 20
yea
rs- r
adic
al su
rger
y: m
argi
nal/s
egm
enta
l re
sect
ion,
rate
of r
ecur
renc
e: 3
3%
mor
e th
an 1
yea
rsBe
nign
mes
ench
ymal
odo
ntog
enic
tum
ors
Odo
ntog
enic
fibr
oma
asym
ptom
atic
, but
larg
e w
ith p
ain,
bo
ny e
xpan
sion
,- R
adio
logi
cal f
eatu
res u
nioc
ular
or
mul
tiocu
lar
- cor
ticat
ed m
argi
n
cellu
lar o
r col
lage
nous
con
nect
ive
tissu
e w
ith v
aryi
ng a
mou
nts o
f in
activ
e-lo
okin
g od
onto
geni
c ep
i-th
elia
l isl
ands
hard
tiss
ue fo
rmat
ion
may
obs
erve
d
desm
opla
stic
fibro
ma,
Odo
ntog
enic
m
yxom
a, d
esm
opla
stic
amel
o-bl
asto
ma,
am
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oma:
pe
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ral
- Tre
at o
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tral o
dont
ogen
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ma:
enu
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need
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rgic
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is 5
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ectio
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of c
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with
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e th
erap
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llow
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inco
mpl
ete
exis
ion
3621Molecular Biology Reports (2021) 48:3617–3628
1 3
radiology provide clinical diagnosis, but cystic lesions, tiny biopsies and determination of malignancy changes are some problems [7]. Also, over/under expression of some genes are reported as molecular marker in odontogenic tumors [8]. In this manner, specific markers help us in the correct diagno-sis of special types of odontogenic tumor, and it increases our knowledge about pathogenesis and molecular genetic features of these lesions. In this study, we describe immuno-histochemical and molecular markers in diagnosis of odonto-genic tumors and investigate recent studies based on “omics” that provide more information about prognosis and therapeu-tic approach of these tumors in addition to diagnosis.
Diagnostic markers in odontogenic tumors
Immunohistochemical markers in diagnosis of odontogenic tumors
Immunohistochemistry (IHC) is an immunostaining tech-nique that detected antigens (proteins) by binding antibodies in cells or tissue. The main benefit of IHC is detection of a specific target following antibody-antigen interaction and can apply in diagnosis of cancerous tumor subsequent to proliferation or cell death. In addition, location and distri-bution of expressed protein are emerged in various parts of tissue. For instance, it was reported significant expression of podoplanin in invasive odontogenic tumors by immunohisto-chemistry technique that emphasized the diagnostic role of this marker on neoplastic behavior [9]. Also, overexpression of MDM2 and p53 was demonstrated in solid multicystic ameloblastoma (SMA) and keratocystic odontogenic tumor (KOT) as IHC markers [10]. In addition, histological fea-tures of the lesion can be helpful in differential diagnosis of rare extension cases such as calcifying epithelial odon-togenic tumor (CEOT) or Pind-borg tumor that expand to the maxillary sinus [11]. The high expression of Cripto-1 or teratoma-derived growth factor 1 (TDGF-1) in almost of aggressive odontogenic lesions proposed involvement of this molecules in ethiopathogenesis [12].
So, IHC seems to be useful for evaluation of tumors by molecular biomarkers. In this manner, Immunohistochemi-cal features of odontogenic tumors beside the clinical fea-tures and radiological finding can help us to determine the correct diagnosis. Because the correct diagnosis helps us for better patient management in therapy. Some side effects of radiotherapy for head and neck cancers include xerostomia, dental caries and oral ulcers that affect oral intake and dif-ficulty in speech. Moreover, radiotherapy increases osteo-sarcoma and oral infection like oral candidiasis because stomach reflex manifests following nausea and vomiting [13]. So, biomarker diagnosis plays a critical role in patient management. There are restricted studies to share results of Ta
ble
1 (c
ontin
ued)
Odo
ntog
enic
tum
orC
linic
al fe
atur
eH
istop
atho
logi
c fe
atur
eD
iffer
entia
l dia
gnos
isPr
ogno
sis a
nd tr
eatm
ent
Cem
ento
blas
tom
a- >
60%
cas
es w
ith p
ain
or sw
ellin
gR
adio
paqu
e m
ass w
ith su
rrou
ndin
g ra
diol
ucen
t rim
fuse
d to
the
apex
of
a to
oth,
usu
ally
the
man
dibu
lar
first
mol
ar (5
0%) o
r a p
rem
olar
- Tee
th a
re g
ener
ally
vita
l
Prol
ifera
tion
of c
emen
tobl
asts
(lar
ge,
ecce
ntric
nuc
lei
(slig
htly
aty
pica
l) w
ith d
ispe
rsed
ch
rom
atin
and
smal
l nuc
leol
isi
mila
r to
oste
obla
sts),
whi
ch d
epos
it ce
men
tum
(oste
oid-
like)
, wov
en
bone
-like
mat
eria
l in
mas
ses
Resti
ng a
nd re
vers
al li
nes a
re o
ften
pres
ent,
and
the
atta
ched
root
may
be
reso
rbed
- Oste
obla
stom
a- C
emen
toos
seou
s dys
plas
ia- H
yper
cem
ento
sis
- Oste
osar
com
a
- Exc
isio
n or
rese
ctio
n of
the
tum
or
with
the
toot
h- 1
0–20
% ra
te o
f rec
urre
nce
Cem
ento
-oss
ifyin
g fib
rom
a (C
OFs
)In
toot
h be
arin
g ar
eas o
f the
jaw
s w
ith o
dont
ogen
ic o
rigin
Pain
less
exp
ansi
on o
f buc
cal a
nd
lingu
al p
late
s of t
he a
ffect
ed b
one
Larg
e le
sion
s exp
and
the
infe
rior
bord
er o
f man
dibl
e or
floo
r of t
he
max
illar
y si
nus
Mor
e ra
diop
aque
ove
r tim
e
Enca
psul
ated
Hyp
er c
ellu
lar fi
brob
lasti
c sto
ma
and
varia
ble
amou
nt o
f cal
cifie
d str
uctu
reO
steob
lasti
c rim
min
g of
the
bone
tra
becu
lae
- Cem
ento
-oss
eous
dys
plas
ia- F
ibro
us d
yspl
asia
A sl
ow g
row
ben
ign
neop
lasm
Exci
ted
by c
onse
rvat
ive
surg
ical
No
recu
rren
ce in
mos
t cas
es
3622 Molecular Biology Reports (2021) 48:3617–3628
1 3
diagnostic proteins in odontogenic tumors, and some of them are mentioned in Table 2 [14, 15].
Potential molecular markers in diagnosis of odontogenic tumors
The etiology of odontogenic tumors is not exactly deter-mined, but the result of next-generation sequencing dem-onstrated specific mutation improved the biology process in tumorigenesis of odontogenic tumors. They involve in cell proliferation and differentiation, control of cell cycle, regu-lation of tooth development or be growth factor and recep-tors, telomerase, apoptotic factors and extracellular matrix remodeling [16]. Most of them that involve in the molecular pathogenesis of odontogenic tumors are oncogene or tumor suppressor genes that we mentioned in Table 3 [17–19]. On the other hand, post transcriptional events such as methyla-tion influences gene activity without any changes in DNA sequence. In this manner, DNA methylation and chromatin remodeling by histone modification inhibit recruitment of splicing or transcription factors. So imprinting or suppress of gene expression result in tumor development [20]. Thus, the tumor biology is affected by the changes in the genome and epigenome.
In addition, some non-coding RNAs like micro-RNAs—small noncoding RNA with 21–25 nt—have regulatory role and impact odontogenesis. For example, miR-16–1 and miR-15a play tumor suppressor role by repression of BCL-2 gene and induce apoptosis. It was shown that the expression of BCL-2 is increased in KOT, but the expression of mir-16–1 and mir-15a are reduced [21]. Profile of micro-RNA expres-sion emerged 40 micro-RNAs with different expression in ameloblastoma compare to control group [22].
Long-noncoding RNA (lncRNA) is another regulatory molecule—more than 200 nt in length—that participates in chromatin modulation and affects transcription and transla-tion [23]. Result of RNA microarray analysis demonstrated LINC-340 up regulated in ameloblastoma and associated with the size of the tumor [24]. Furthermore, another class of small non-coding RNA (snoRNA) that modified ribo-somal RNA positively correlated to size of tumor such as SNORA11 in ameloblastoma [24]. This significant differ-ent expression of the molecular marker proposes potential role of them in etiopathogenesis of odontogenic tumors and suitable candidate in diagnostic and therapeutic approaches.
In recent years “-omics” studies discover potential can-didate biomolecules in pathogenesis of odontogenic lesions [19]. “-omics” technology provides comprehensive biologi-cal information that analyses specific types of molecules. For example, genomics, epigenomics, transcriptomics, proteom-ics and metabolomics are different levels of this technol-ogy that evaluates alterations in DNA, non-DNA sequence, RNA, proteins and metabolites, respectively (Fig. 1) [25].
This technology enables to detect molecular mechanism, etiology, for better management of affected odontogenic patients. In this regard, some studies exhibit the result of “-omics” in odontogenic cases that can apply in diagnostic approaches [19]. For example, protein plays a regulatory role during cell function and because of dynamic protein interac-tion in a complex, proteomics-based technology provides identification and quantification of proteome. So it will be applicable in diagnostic approaches in addition to progno-sis and therapeutic to vaccine development [26]. In odonto-genic tumors, proteomics emerged significant alternation of protein levels in some classified types. For instance, it was reported the increasing level of AIDA protein in odontogenic keratocyst [27].
Understand of molecular pathology helps us to develop a therapeutic approach in addition to diagnosis. For instance, immunostaining of ameloblastoma cases demonstrated p53 and MDM2 was high in odontogenic keratocyst (OKC) followed by solid multicystic ameloblastoma (SMA) [10]. Also, immunoexpression of PTEN in ameloblastoma cases showed significant reduction in immunoactivity [28].
Discussion
The pathologists deal with challenges in diagnosis of odontogenic tumors because they are rare and obtained experiences are difficult to be evaluated. The diagnosis is determined based on morphology, clinical manifestation and radiological features, but the outcome of many studies demonstrated immune-histochemical marker can help us to diagnose of some odontogenic tumors. Although these mark-ers are neither specific nor sensitive enough, but analysis of gene expression can help us in definitive confirmation of diagnosis. Based on the molecular pathway that lesions are involved, expression of some genes changes as overex-pression or aberrant expression. In addition, “-omics” tech-nology detected specific molecular alternation associated with etiology of disease. But low frequency of odontogenic lesions restricted researches to discover many aspects of disease. Whole genome sequencing and transcriptomics in ghost cell odontogenic carcinoma manifested involving of NOTCH and SHH pathways including increased copy num-ber of SHH, GLI1, JAG1, DTX3, and HEY1 that result in overexpression of them. Furthermore, fusion of TCF4 and PTPRG genes defect tumor suppressor activity of tyrosine phosphatase receptor type G protein [29].
Understand of odontogenic pathogenesis of odontogenic tumors assistances with diagnosis of malignant transfor-mation, development and progression of lesions. It seems if that tissue samples after collection embedded in paraf-fin or formalin-fixed can be saved as a bio bank for future evaluation. Recent technologies provide easy access to
3623Molecular Biology Reports (2021) 48:3617–3628
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Table 2 Summery of immune-histochemical odontogenic tumor markers
Marker Function Diagnostic marker
Cytokeratin (CK) An intermediate filament ( structural cytoskel-eton protein)
- Odontogenic tumors with epithelial origin express CK14 and CK19
- AOTs express CK 5, 14, 19- Ameloblastoma express CK 5, 14, 19, 56- Clear cell odontogenic carcinoma express
CK5, 6, 14, 19 and pancytokeratin AE1/AE3- Primordial odontogenic tumor strongly posi-
tive for CK5, 14 and pancytokeratin AE1/AE3- DGCT epithelial cells express CK5, 7, 14, 19- CEOT express CK5, 6- Odontogenic fibroma positive for AE1/3,
K8/18, K14, and K19Amelogenin Enamel matrix protein that organize enamel
rods and mineralize enamel- Express in odontogenic tumors with epithelial
origin such as ameloblastoma, AOT, CEOT, AF, malignant ameloblastoma and ameloblas-tic carcinoma
Ameloblastin (AMBN) A cell adhesion molecule that inhibit amelo-blasts proliferation
Ameloblastoma, AOT, SOT, CEOT
Calretinin (calbindin-2) A calcium-binding protein that modulate intra cellular Ca++ ion
- Express in solid and unicystic ameloblastomas
Bone morphogenetic proteins (BMPs) Play role in cell proliferation, differentiation, chemotaxis, extracellular matrix production, apoptosis and mesenchymal cell differentia-tion
formation of calcified dental tissues and odon-togenic tumor development
- Express in epithelial odontogenic tumors such as ameloblastomas and adenomatoid odonto-genic tumor
Tenascin A glycoprotein play role in cell–cell and cell-extracellular matrix interactions
- Form calcifying mass in CEOT, ameloblastic fibro-odontoma (AFO) and odontoma
Nestin A intermediate filament (structural cytoskel-eton protein)
- Odontogenic ectomesenchyme in mixed tumours such as AF, AFO, ameloblastic fibro-dentinoma (AFD) and ameloblastic fibrosar-coma (AFS)
High-mobility group A protein 2 (HMGA2) Non-histone chromatin factor - Over express in odontogenic mesenchymal tumors such as OM, odontogenic myxofi-broma
Basement membrane proteins Distinction of extracellular matrix (ECM) and epithelium, adjacent connective tissue stroma
- Express in odontogenic tumors epithelium such as laminin
Cytoskeleton remodeling protein (moesin and RhoA)
Connect the plasma membrane and cytoskel-eton with maintaining and remodeling them
- Strongly express in odontogenic epithelial cells and involvement in development of benign odontogenic lesions
Vimentin A intermediate filament (structural cytoskel-eton protein)
- Express in mesenchymal cell of primordial odontogenic tumor, central odontogenic fibroma
CD138 (syndecan-1) and MMP9 CD138: A heparin sulphate proteoglycan controls tumor cell growth, adhesion and differentiation
MMP9: involved in the degradation of the extracellular matrix
- Express in tumor and stromal cell of DGCT
Calretinin Play role in message targeting and intracellu-lar calcium buffering
Ameloblastoma
CD68, lysozyme Present with macrophage, lysis central odontogenic fibromaS100 A family of calcium-binding proteins Odontogenic myxomaKi-67 Cell proliferation marker Ameloblastic carcinoma, Ameloblastoma
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genome, transcriptome or proteome of saved samples with sufficient integrity and quality [30]. As another strategy, organotypic cultures were suggested in an experimental model for detection of molecular aspects of odontogenic tumors. The organotypic cultures provide ex vivo imitated neoplastic microenvironment with suitable reproduction of the growth pattern. In addition, organoid represents in vitro tumor model-study for metastasis and invasion, drug screening, immunotherapy, clinical trial, hallmarks association with prognosis and evolution of personal-ized anti-cancer therapy [31]. Organoid provide optional treatment for patientʹ s tumor attention to site, stage and personal factors and variation in their genetic profile as personalized medicine. For example, different drug dosage or combination therapy can be applied in an organoid and the outcome determined the best choice for therapy [32].
Further, organoid led to collect biobank from differ-ent tumor cell lines and study genome features follow-ing cell propagation and development, so alternation in genetic profile such as mutations can be studied between tumouroid line and a derived tumor [33]. Also, we pro-pose application of biobank with collection of odontogenic lesion types from different geographical regions can help us to define a distinct profile change in the genome for therapy.
The first study with long-term 3D primary culture was performed for odontogenic myxoma and the cemento-ossi-fying fibroma with cell expansion more than one month [34]. More investigation is continued for human head and neck tumors with organoid. For example, 3D organoid provides target therapeutic screening based on a non-surgical method
to evaluate ameloblastoma pathogenesis and progression for BRAF and LGR5 inhibition [35]. More knowledge about biology and molecular behavior of odontogenic tumors increases our information for better understanding of their nature. Also, we think more investigation and studies are needed to gain these knowledges that can shift therapeutic approaches to target therapy. Detection of genetic factors that are involved in molecular pathogenesis of odontogenic tumors helps us in target therapy, special gene therapy when surgical treatments are contraindicated [36]. In this man-ner we can find ways for other odontogenic lesions as non-surgical therapeutic approaches (Fig. 2).
Conclusion
The restricted origin of odontogenic tumors (epithelial, mes-enchymal or mixed) might appear with similar morphology and histochemical features in differential diagnosis. So, mistaken in diagnosis provides improper treatment because some odontogenic tumors need invasive therapy but others not. The molecular advanced technology like next-genera-tion sequencing or “omics” can identify all aspects of tumor changes and help us to consider more candidates in diagno-sis, prognosis and therapeutic approaches. Target therapy in oral pathology needs more investigation, and it seems ethio-pathological information of familial odontogenic tumors in different geographical regions can help us to modify our attitude to pathogenesis of these lesions.
Table 2 (continued)
Marker Function Diagnostic marker
P63, epithelial membrane antigen (EMA), Filaggrin
P63: transcription factor for teeth and mam-mary glands development
EMA: transmembrane muci expressed on epi-thelial cells
Filaggrin: filament-associated protein that binds to keratin fibers
clear cell odontogenic carcinoma
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Table 3 Alternation of genetic profile in odontogenic tumors
Odontogenic tumor type Alternation in gene expression Current gene mutation Rare gene mutation
Ameloblastic carcinoma Overexpression of SOX2 and PITX2 (TF in Wnt pathway)
High level of ki-67 proteinIncreased POLR2J, CDKN2C and
decreased EIF3S5 expression
63% of cases BRAF (V600E),16–39% smoothened (SMO)
FGFR2, RAS (KRAS, NRAS, HRAS), PIK3CA, CTNNB1, SMARCB1
Primary intraosseous carcinoma, NOS
- Increased NF-6, epidermal keratin type II, MEF2C transcription factor, metalloproteinase, tyrosine phosphatase CIP2, TGFB BP, mitogen inducible gene-2 and oncofetal antigen 5T4 expression
- Decreased epidermal keratin types 1,13,15,16, TGFB3R, differentiation dependent A4 protein, ribosomal protein L3, L8, L28, L29, L31, L35, S3, S5, S10, S24, ZFP, DNA BP FKHL15, PRAD1 and ARF-activated phosphatidylcholine specific phospholipase D1a expression
Sclerosing odontogenic carcinoma Clear cell odontogenic carcinoma Increased ADAM28, FGF9,
S100A7, PTCH1, MMP1,2,12 ≥ 80% show EWSR1 rearrange-
mentATF1 as translocation partner,
BRAF (V600E) Ghost cell odontogenic carcinoma Overexpression of p53 UBR5, APC (related to Gardner
syndrome: familial colorectal polyposis)
Ameloblastoma Overexpression of SMO, BRAFIncreasing ODAM, FOS and
decreasing CTBP2, STK19 expression
≥ 90% demonstrated MAPK pathway mutation (most BRAF V600E), others: RAS (KRAS, NRAS, HRAS), FGFR2
Non-MAPK pathway: SMO, SMARCB1, CTNNB1, PI3CA
Ameloblastoma, unicystic type (UAM)
BRAF (V600E)
Ameloblastoma, extraosseous/peripheral type
β-catenin mutation in Wnt pathway
Metastasizing ameloblastomaSquamous odontogenic tumor NOTCH receptor and ligands,
ameloblastin (AMBN), metal-lotheionein
Classify epithelial odontogenic tumor (CEOT)
Over expression of AODAMLoss of p53 expression
PTCH, p63, EGFR, bcl-2 SHH, Gli1, Gli2
Adenomatiod odontogenic tumorBenign mixed epithelial and mesenchymal odontogenic tumorsAmeloblastic fibroma (AF) BRAF (V600E)
Lost genetic loci in p53 (17p13) and CHRNB1 (17p13)
Primordial odontogenic tumor Increasing DMP1, decreasing IBSP and BGLAP expression
Odontoma Odontoma, compound type Odontoma, complex type
Manifect in Gardner syndrome: familial colorectal polyposis
Dentinogenic ghost cell tumorBenign mesenchymal odontogenic tumorsOdontogenic fibromaOdontogenic myxoma/myxofi-
bromaDownregulation of PRKAR1A
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Table 3 (continued)
Odontogenic tumor type Alternation in gene expression Current gene mutation Rare gene mutation
CementoblastomaCemento-ossifying fibroma Increasing CTNNB1, TCF7, NKD1,
WNT5A, HMMR and decreas-ing CTNNBIP1, FRZB, FZD6, RHOU, SFRP4, WNT10A, WNT4 expression
mutation in CDC73 (HRPT2) gene
Fig. 1 Different main levels of “-omics” technology for evaluation of comprehensive molecules in cell including genetic variants in DNA sequence (Genomics), non-DNA sequence alternation such as histone modification and methylation (Epigenomics), analysis of expression and structural changes in RNA and variants like splice sites (Tran-
scriptomics), evaluation of expression, modification and net protein interactions (Proteomics) and description of functional metabolites in cell (Metabolomics). The mix of different type of “-omics” technol-ogy can help us in diagnose, prognoses and therapeutic approaches of tumors
3627Molecular Biology Reports (2021) 48:3617–3628
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Declarations
Conflicts of interest The authors declare that there are no conflicts of interest.
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